Cognitive impairment associated with primary or metastatic brain tumors and related treatments, including radiation therapy, occurs in a significant proportion of patients with 10% of patients developing progressive dementia, and 50% to 90% showing deficits when assessed with sensitive tests of cognitive function. About 20-40% of the >1,300,000 new cancer patients diagnosed in 2004 developed brain metastases (mets). At least 200,000 cancer patients/year receive whole brain irradiation (WBI) for brain mets, while 15,000 receive partial (P) or WBI for the treatment of a primary brain tumor. Clinically, patients frequently complain of a neurocognitive symptom cluster that includes difficulty remembering, organizing thoughts, and language fluency. This neurocognitive symptom cluster in turn is associated with significantly reduced quality of life and mood. Presently, there are very few available treatments for neurocognitive symptoms in patients who have received cranial irradiation;and no known preventive interventions exist. Administration of selective inhibitors of acetylcholinesterase like donepezil (Aricept) has proven effective in improving neurocognitive functioning and behavioral symptoms in patients with Alzheimer's disease. A recent prospective, open-label Phase 2 study of donepezil in long-term (>6 month) survivors of P/WBI conducted by this research team demonstrated a significant reduction in neurocognitive symptoms, as well as a significant improvement in mood, fatigue and quality of life. We hypothesize that the AChE inhibitor, donepezil, will lessen the neurocognitive symptom cluster and improve quality of life and mood in long-term survivors of brain irradiation. Thus we propose a 24-week, Phase III, randomized, double-blind, placebo-controlled trial of donepezil with 200 patients following partial or whole brain irradiation. The significance of this application is that it represents the first prospective controlled trial of donepezil (a well-tolerated drug with proven efficacy for reducing cognitive and functional impairment in Alzheimer's dementia) in survivors of partial or whole brain irradiation. RELEVANCE: This study will demonstrate whether a drug that helps dementia patients will also help to reduce cognitive impairment following brain radiation treatment for tumors. If successful the study will offer physicians a treatment for radiation-induced cognitive impairment which also may improve mood and quality of life.